Regulatory T cells (also known as “suppressor T cells” or “Tregs”) are specialized populations of T cells that act to suppress activation of the immune system and thereby maintain immune system homeostasis and tolerance to self-antigens. Regulatory T cells can occur naturally (also referred to herein as “nTregs”) or they can be induced in peripheral lymphoid tissues (also referred to herein as “iTregs”).
Naturally occurring, thymus derived regulatory T cells play crucial roles in controlling autoimmune disease by maintaining immunological homeostasis and self-tolerance. Adoptive transfer of nTregs has been shown to prevent many autoimmune diseases, including experimental autoimmune encephalomyelitis, colitis, diabetes and gastritis. However, the effect of transferred nTregs once a disease is established is less predictable. For example, in lupus, the effect of transferred nTregs is modest if the transfer occurs after the disease is established. Similarly, in collagen-induced arthritis, it has been shown that nTreg transfer can prevent but cannot modify the established disease. A possible reason for the lack of effect with nTregs once the disease is established may be due to an instability of FOXP3 in an inflammatory milieu, conversion of nTregs to pro-inflammatory effector cells, or an acquired resistance of T effector cells to nTregs.
For therapeutic applications, it would be advantageous to have methods and compositions for expanding nTregs with stabilized phenotypes that remain resistant to effector cell conversion after expansion.